The overall goals of this proposal are to elucidate the role receptors play in the mechanism of action of glucocorticoid hormones and to apply the molecular concepts derived from these studies to gain further understanding of related clinical problems. Three lines of inquiry will be pursued. The first section deals with receptor heterogeneity -- the inter-relationships of glucocorticoid receptors in various tissues and multiple heterogeneous receptors within a given tissue. This section is also concerned with the issue of how glucocorticoid enzyme induction in different tissue, mediated via homogeneous receptors, can be heterogeneous. The section also explores the potential functions of an intracellular corticosterone receptor (Type III). The second section deals with receptor regulation -- a control mechanism whereby other hormones, hormone antagonists or stress may modulate the amplitude of the response to glucocorticoids. This section is also concerned with exploring the mechanism of action of hormone antagonists and defining why glucocorticoid requirements are increased during stress. The third section deals with non-steroidal anti-inflammatory drugs --the activity of these drugs may, in part, be mediated via interaction with mineralocorticoid and glucocorticoid receptors. This section is also concerned with whether some of the anti-inflammatory activitiy of glucocorticoids is mediated by the inhibition of prostaglandins. A multiphasic experimental design is planned subjecting several different but related aspects of receptor function to investigation. Studies will be performed with rats using 3H-steroids and employing a variety of binding techniques to evaluate hormone-receptor relationships. In vivo, in vitro and tissue culture systems will be utilized. It is hoped that the data obtained by this approach will significantly add to our understanding of the role receptors play in glucocorticoid action.